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The development of robust biosensing strategies that can be easily implemented in everyday life remains a challenge for the future of modern biosensor research. While several reagentless approaches have attempted to address this challenge, they often achieve user-friendliness through sacrificing sensitivity or universality. While acceptable for certain applications, these trade-offs hinder the widespread adoption of reagentless biosensing technologies. Here, we report a novel approach to reagentless biosensing that achieves high sensitivity, rapid detection, and universality using the SARS-CoV-2 virus as a model target. Universality is achieved by using nanoscale molecular pendulums, which enables reagentless electrochemical biosensing through a variable antibody recognition element. Enhanced sensitivity and rapid detection are accomplished by incorporating the coffee-ring phenomenon into the sensing scheme, allowing for target preconcentration on a ring-shaped electrode. Using this approach, we obtained limits of detection of 1 fg/mL and 20 copies/mL for the SARS-CoV-2 nucleoproteins and viral particles, respectively. In addition, clinical sample analysis showed excellent agreement with Ct values from PCR-positive SARS-CoV-2 patients.

BACKGROUND: The COVID-19 pandemic and associated social distancing measures have profoundly impacted society and social contact patterns, with older people disproportionately affected. Concerns have been raised about a resulting pandemic of loneliness in older people, although the current evidence is mixed. This study provides a unique perspective on the prevalence of loneliness in a population cohort of older people before the pandemic, followed up after the introduction of social restrictions. METHODS: Data analysis was conducted using Wave 3 of the longitudinal Cognitive Function and Aging Study II (2018-2019) and a sub-study focusing on experiences during the COVID-19 pandemic (2020). The sample comprised 379 adults aged over 75 living in Cambridge, Newcastle, and Nottingham. Multivariable binary logistic regression was conducted to identify correlates of prevalent loneliness, adjusted for confounding covariates, during the pandemic. The prevalence of loneliness during the pandemic was compared to loneliness in 2018-2019. RESULTS: Prevalence of loneliness in this sample during the pandemic was 25.1% (95% CI 20.9%-29.7%) compared to 17.2% (95% CI 13.7%-21.3%) in 2018-2019 (χ2 = 14.1, p

Fiber reinforced polymer composites (FRPCs) are valued for their high strength and lightweight and have found applications from aerospace to renewable energy. Additive manufacturing (AM, or 3D printing) of FRPCs is of great interest in recent years due to the manufacturing flexibility offered by AM. Direct ink write (DIW) 3D printing is a popular choice for FRPC 3D printing due to its low cost and open framework for broad material choices. However, previously explored techniques for AM of FRPCs are hindered by heavy reliance on fiber orientation dictated by extrusion toolpath and often require specialized hardware to print FRPCs with low viscosity and long cure time thermoset epoxy matrices. In this paper, we introduce a single-stream hybrid DIW AM technique for the creation of mechanically robust FRPC functional structures where the matrix is DIW 3D printed, and pre-epoxy impregnated (prepreg) woven carbon fiber (CF) fabrics are robotically placed. Additionally, functional components, such as conductive elements, can be readily integrated. We investigated the impact of prepreg woven CF reinforcement on a two-stage photo-thermal thermoset resin matrix on the mechanical characteristics of manufactured FRPCs. We also combined these efforts to fabricate functional structures, including strain sensors for in-situ deformation monitoring, heating elements, and embedded light sensors. This study found that the proposed single-stream hybrid DIW AM process could be a facile approach to fabricate high-strength FRPC functional structures.

Background: Although numerous studies have reported a decrease in dementia risk in the last two decades, it is unclear whether dementia-free cognitive function is also changing across generations. Objective: The objective was to systematically evaluate the published data on generational differences in cognitive function in the older population. Methods: Searches were performed on PubMed, Embase, and PsychInfo for articles published in English before 28 June 2021. Included studies were from population-based samples that reported generational differences in cognition in individuals without dementia, aged ≥60 years. Results: 28,101 studies were identified and 15 selected covering the period from 1971 to 2015: including studies from China, Europe, and the USA. The results show generally consistent findings of improvements or stability in dementia free cognitive function in later versus earlier born generations, but not for all cognitive domains. Prevalence of mild cognitive impairment and cognitive impairment no dementia has remained stable in the USA, UK, and China over the last two decades. Results: Prevalence of vascular related mild cognitive impairment has increased in China. Improvements in cognition may only partially be explained by increased educational attainment across generations. Conclusion: This review provides evidence for generational effects in dementia-free cognitive function, predominately stability or improvements in performance, in later compared to earlier born individuals across different world regions. There is an urgent need to determine the factors driving such changes and whether they are being experienced in all world regions, particularly low- and middle-income countries where the burden of cognitive impairment is greatest and rising.

Despite their unique optical and electrical characteristics, traditional semiconductor quantum dots (QDs) made of heavy metals or carbon are not compatible with many biomedical applications. Cytotoxicity and environmental concerns are key limiting factors that prevent their widescale transition from laboratory research to real-world medical applications. Recently, advanced InP/ZnSe/ZnS QDs have emerged as excellent alternatives to traditional QDs due to their lower toxicity and optical properties; however, they fall short of traditional QDs with respect to their versatility for bioconjugation (i.e., surface chemistry limitations causing unstability in aqueous environments). In this work, we construct a road map for generating, for the first time, highly efficient bio-templated InP/ZnSe/ZnS-aptamers (QDAPT) with long-term stability and high selectivity for applications in targetting bacterial membrane proteins. Our QDAPTs show fast binding reaction kinetics (less than 5 minutes), high brightness, and high shelf-life stability (3 months) after biotemplation in aqueous solvents. We also demonstrate the detection of bacterial membrane proteins on common surfaces using a hand-held imaging device, which attests to the great potential of this system for incorporation into future biomedical technologies.

Purpose:OBI-3424 is a highly selective prodrug that is converted by aldo-keto reductase family 1 member C3 (AKR1C3) to a potent DNA-alkylating agent. OBI-3424 has entered clinical testing for hepatocellular carcinoma and castrate-resistant prostate cancer, and it represents a potentially novel treatment for acute lymphoblastic leukemia (ALL).Experimental Design:We assessed AKR1C3 expression by RNA-Seq and immunoblotting, and evaluated the in vitro cytotoxicity of OBI-3424. We investigated the pharmacokinetics of OBI-3424 in mice and nonhuman primates, and assessed the in vivo efficacy of OBI-3424 against a large panel of patient-derived xenografts (PDX).Results:AKR1C3 mRNA expression was significantly higher in primary T-lineage ALL (T-ALL; n = 264) than B-lineage ALL (B-ALL; n = 1,740; P < 0.0001), and OBI-3424 exerted potent cytotoxicity against T-ALL cell lines and PDXs. In vivo, OBI-3424 significantly prolonged the event-free survival (EFS) of nine of nine ALL PDXs by 17.1–77.8 days (treated/control values 2.5–14.0), and disease regression was observed in eight of nine PDXs. A significant reduction (P < 0.0001) in bone marrow infiltration at day 28 was observed in four of six evaluable T-ALL PDXs. The importance of AKR1C3 in the in vivo response to OBI-3424 was verified using a B-ALL PDX that had been lentivirally transduced to stably overexpress AKR1C3. OBI-3424 combined with nelarabine resulted in prolongation of mouse EFS compared with each single agent alone in two T-ALL PDXs.Conclusions:OBI-3424 exerted profound in vivo efficacy against T-ALL PDXs derived predominantly from aggressive and fatal disease, and therefore may represent a novel treatment for aggressive and chemoresistant T-ALL in an AKR1C3 biomarker-driven clinical trial.

Power analyses are often used to determine the number of animals required for a genome-wide association study (GWAS). These analyses are typically intended to estimate the sample size needed for at least 1 locus to exceed a genome-wide significance threshold. A related question that is less commonly considered is the number of significant loci that will be discovered with a given sample size. We used simulations based on a real data set that consisted of 3,173 male and female adult N/NIH heterogeneous stock rats to explore the relationship between sample size and the number of significant loci discovered. Our simulations examined the number of loci identified in subsamples of the full data set. The subsampling analysis was conducted for 4 traits with low (0.15 ± 0.03), medium (0.31 ± 0.03 and 0.36 ± 0.03), and high (0.46 ± 0.03) SNP-based heritabilities. For each trait, we subsampled the data 100 times at different sample sizes (500, 1,000, 1,500, 2,000, and 2,500). We observed an exponential increase in the number of significant loci with larger sample sizes. Our results are consistent with similar observations in human GWAS and imply that future rodent GWAS should use sample sizes that are significantly larger than those needed to obtain a single significant result.

We describe a proof-of-concept study in which peptide-bound enamine and thiourea catalysts are used to facilitate the conjugate addition of cyclohexanone to nitroolefins. Our bifunctional peptide scaffold is modified to optimize the local environment around both catalysts to enhance both reactivity and enantioselectivity, affording selectivities of ≤95% ee. Circular dichroism, nuclear magnetic resonance nuclear Overhauser effect studies, and molecular dynamics simulations verify the helical structure of our catalyst in solution and the importance of the secondary structure in catalysis.

Background Elexacaftor-tezacaftor-ivacaftor (ETI) improves pulmonary health and chronic rhinosinusitis (CRS) for people with cystic fibrosis (PwCF), however its impact on olfaction has not been investigated. Olfactory dysfunction impairs quality-of-life (QOL). This study evaluated the impact of ETI on multiple olfactory metrics. Methods Adult PwCF/CRS with CF transmembrane conductance regulator genotype F508del/F508del or F508del/minimal function who clinically initiated ETI participated in a prospective, observational study. Endpoints included changes after 6 months of ETI in quantitative olfactory function (Smell Identification Test, SIT), olfactory QOL (Questionnaire of Olfactory Disorders, QOD) and percent olfactory cleft opacification (%OCO), representing superior nasal cavity inflammation where afferent olfactory neurons are concentrated. Results 30 PwCF/CRS met inclusion criteria; 25 completed the study. Mean ETI adherence was 93%. At baseline, participants were hyposmic (mean SIT 31.3), had significant %OCO (mean 65.6%), yet reported non-impaired olfactory QOL (mean QOD 6.1). At follow-up, mean SIT worsened mildly (p=0.009), mean %OCO remained stable (p=0.46), and mean QOD improved modestly (p=0.008). No outcomes were impacted by prior modulator use, genotype, nasal polyps, or CF-related diabetes. Prior sinus surgery was associated with QOD improvement (p=0.04). Increased (worse) baseline QOD scores and %OCO were associated with greater improvements (p Conclusions ETI was not associated with improvement in quantitative olfaction or olfactory cleft opacification after 6 months. PwCF/CRS have hyposmia but do not report impairment in olfactory QOL. Further study to investigate mechanisms explaining olfactory dysfunction and whether olfaction improves with greater duration of ETI or in younger age groups is warranted.